The heme oxygenase inducer hemin protects against cardiac dysfunction and ventricular fibrillation in ischaemic/reperfused rat hearts: role of connexin 43.
Cardiac expression of cytoprotective gene heme oxygenase-1 (HO-1) is modulated by ischaemia and reperfusion (I/R). We therefore hypothesized that pretreatment with hemin, an inductor of HO-1, would precondition the heart against post-ischaemic dysfunction and ventricular fibrillation (VF). Male Wistar rats were given either hemin or HO enzyme inhibitor zinc protoporphyrin IX (ZnPP IX). Isolated hearts were subjected to 30 min global ischaemia followed by 120 min of reperfusion or were aerobically perfused in a time-matched non-ischaemic protocol. Control animals received no pretreatment. Compared to non-perfused controls, pretreatment with hemin increased HO-1 mRNA 13-fold (p<0.001) and HO-1 protein 3.5-fold (p<or=0.001), improved post-ischaemic aortic flow, coronary flow, LVDP and -Dp/dt (p<0.01) and decreased LVEDP (p<0.001) and the incidence of VF (p = 0.001). The improved post-ischaemic cardiac function and reduction of VF were accompanied by a higher total connexin 43 (Cx43) level compared to non-pretreated and ZnPP IX pretreated hearts, and accumulation of non-phosphorylated gap junction protein Cx43 in intercalated discs and lateral plasma membrane of cardiomyocytes. Cardioprotection by HO-1 appeared to be independent of cGMP. Administration of ZnPP IX had no effect on cardiac function or VF. Our results show that pharmacological modulation of HO-1 pathway may provide a new therapeutic approach to protect the heart against post-ischaemic dysfunction and I/R-induced VF possibly by a Cx43 dependent mechanism.
Lakkisto
Päivi
P
Department of Clinical Chemistry, Helsinki University Central Hospital, Finland. paivi.lakkisto@helsinki.fi
Csonka
Csaba
C
Fodor
Gabriella
G
Bencsik
Péter
P
Voipio-Pulkki
Liisa-Maria
LM
Ferdinandy
Peter
P
Pulkki
Kari
K
D000818:Animals; D001483:Base Sequence; D018031:Connexin 43 / Q000502:physiology*; D017931:DNA Primers; D004790:Enzyme Induction; D006321:Heart / Q000503:physiopathology*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000235:genetics; D006427:Hemin / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D011524:Protoporphyrins / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014693:Ventricular Fibrillation / Q000517:prevention & control*
D018031:Connexin 43; D017931:DNA Primers; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D006427:Hemin; D006419:Heme Oxygenase (Decyclizing)